Parkinson's disease (PD) is a common late onset progressive neurodegenerative disease characterized by degeneration of subcortical neuronal populations, including dopaminergic neurons of substantia nigra, pars compacta (SNpc), and presence of the cytoplasmic inclusions composed of alpha-synuclein in multiple neuronal populations. While the motoric abnormalities are most obvious feature of PD, non-motoric abnormalities, such as dementia, are the most debilitating factors for PD patients. Thus, understanding the neuropathological basis for dementia in PD and other alpha- synucleinopathies are essential for effective therapeutic intervention of these diseases. In this proposal, we aim to understand the neuropathological basis for cognitive dysfunction/dementia in alpha-synucleinopathies such as PD and LBD. Human studies correlate the presence of alpha- synuclein pathology, as well as beta-amyloid pathology, in cortical-limbic areas correlate with dementia in PD/LBD cases. Significantly, we observed PD-like cognitive deficits in transgenic mice expressing A53T mutant alpha-Syn. We will determine the neuropathological basis for cognitive deficit in the A53T transgenic mice and use inducible alpha-synuclein transgenic mouse model to explore the causal links between alpha-synuclein abnormalities, neurodegeneration, and cognitive deficits. We will also study how overt amyloid deposition interacts with alpha-synuclein abnormalities to exacerbate cognitive deficits in A53T transgenic mice. Finally, we will test whether environmental exposure to PD-relevant compounds, such as pesticides, promotes both alpha-synuclein pathology and cognitive dysfunction in mice. Overall, these studies will provide in vivo experimental tests of potential factors that could contribute to dementia in human alpha-synucleinopathies. The results will be directly relevant to the pathogenesis of human alpha-synucleinopathies and lead to new therapeutic approaches to alleviate non-motoric abnormalities associated with PD and other alpha-synucleinopathies.